Cocaine and nicotine abuse remain serious problems in society, with high recidivism rates. When self administered by humans, abused drugs exert powerful, direct pharmacological actions within localized brain regions and circuits, while also interacting with specific cognitive systems. The overall goals of this project are to employ fMRI to define those neuronal systems in the human CNS mediating the actions of these two very addictive agents and to determine how cocaine and nicotine interact with specific cognitive and affective processes. The interplay between where cocaine acts in the human brain and how these circuits overlap with nicotine and other abused agents is poorly understood. Additionally, almost nothing is known regarding their neural pharmacokinetic and pharmacodynamic properties and neurochemical sites and mechanisms of action in humans. Specific Aim I of this proposal addresses these pharmacological issues. However, human drug abuse is not simply explained by where a drug acts in the brain. While the powerful reinforcing and, in the case of cocaine, euphorigenic properties of these drugs are important in drug-seeking and drug-taking behavior, drug administration also engages a complex, poorly understood sequence of behavioral alterations that, taken together, perpetuate drug taking behavior. Specific Aim 2 addresses the effects of cocaine and nicotine on cognitive and affective processes. Since cocaine addicts report selective recall of the high over the crash and exhibit considerable difficulty controlling impulses to use and appropriately weighing risks of use. Therefore, it is hypothesized that acute cocaine will enhance sustained attention and recall for events occurring under the influence of the drug and that corresponding alterations in fMRI activation in attentional networks (frontal, parietal, thalamic) and in memory circuits (hippocampus) will be seen. It is further hypothesized that acute cocaine will impair inhibitory control, concept formation and attention switching with corresponding alterations in specific frontal lobe activation. Finally, we will examine the interaction between acute cocaine administration and affective state to test the hypothesis that the reinforcing properties of the drug are enhanced during times of negative affect and cocaine craving. A better understanding of these processes may lead to better behavioral and/or pharmacological therapeutic interventions for cocaine abuse and recidivism and identify a likely cognitive profile resulting from prolonged abuse to help identify those most at risk for dependence.